Yıl: 2022 Cilt: 28 Sayı: 1 Sayfa Aralığı: 87 - 96 Metin Dili: İngilizce DOI: 10.9775/kvfd.2021.26491 İndeks Tarihi: 13-06-2022

Effect of Tocilizumab on Acinetobacter baumannii Lung Infection in an Immunosuppressed Rat Model

Öz:
Our study aimed to investigate effect of tocilizumab on the lung tissue in the presence of Acinetobacter baumannii infection in immunosuppressed rats. A forty-eight female Wistar albino rats were divided equally into eight groups: Group 1: Healthy (H), Group 2: Immunosuppressed (IM), Group 3: Healthy rats given A. baumannii bacteria (H+BAC), Group 4: Immunosuppressed rats given A. baumannii bacteria (IM+BAC), Group 5: Healthy rats given tocilizumab (H+TCZ), Group 6: Immunosuppressed rats given tocilizumab (IM+TCZ), Group 7: Healthy rats given A. baumannii bacteria and tocilizumab (H+BAC+TCZ), Group 8: Immunosuppressed rats given tocilizumab and A. baumannii bacteria (IM+BAC+TCZ). Fourteen days after the immunosuppression of group 2, 4, 6 and 8 with hydrocortisone, group 3, 4, 7 and 8 were A. baumannii was dropped into the trachea. One hour after A. baumannii application, TCZ was administered to Groups 5, 6, 7 and 8. NF-κB, IL-6 and NLRP3 mRNA expressions were decreased in the IM group compared to the healthy group (P<0.05). Although NF-κB, IL-6 and NLRP3 mRNA expression decreased in the IM+TCZ group compared to the healthy group (P<0.05) NF-κB, IL-6 and NLRP3 mRNA expression increased in the H+TCZ group (P<0.05). Despite decreasing cytokines, A. baumannii has been shown to increase infection-related lung injury. This suggests that in patients currently or recently using steroids, tocilizumab may increase organ damage due to opportunistic infection.
Anahtar Kelime:

Tocilizumab’ın İmmünsüprese Rat Modelinde Acinetobacter baumannii’nin Akciğer Enfeksiyonu Üzerindeki Etkisi

Öz:
Çalışmamızda, immünsüpresyon oluşturulmuş ratlarda Acinetobacter baumannii enfeksiyonu varlığında tocilizumabın akciğer dokusundaki etkisini araştırmayı amaçladık. Toplam kırk sekiz dişi Wistar albino rat sekiz eşit gruba ayrıldı: Grup 1: Sağlıklı (H), Grup 2: İmmünsüprese ratlar (IM), Grup 3: A. baumannii bakterisi verilen sağlıklı ratlar (H+BAC), Grup 4: A. baumannii bakterisi verilen immünsüprese ratlar, Grup 5: Tocilizumab verilen sağlıklı ratlar (H+TCZ), Grup 6: Tocilizumab verilen immünsüprese ratlar (IM+TCZ), Grup 7: A. baumannii bakterisi ve tocilizumab verilen sağlıklı ratlar (H+BAC+TCZ), Grup8: Tocilizumab ve A. baumannii bakterisi verilen immünsüprese sıçanlar (IM+BAC+TCZ). Grup 2, 4, 6 ve 8’in hidrokortizon ile immünosupresyonundan 14 gün sonra, grup 3, 4, 7 ve 8’e A. baumannii suşu trakeaya transtrakeal yolla enjekte edildi. Grup 5, 6, 7 ve 8’e A. baumannii uygulamasından bir saat sonra TCZ verildi. İmmünsüprese grupta (IM) sağlıklı gruba (H) göre NF-κB, IL-6 ve NLRP3 mRNA ekspresyonları azaldı (P<0.05). Her ne kadar TCZ verilen IM grubunda (IM+TCZ) NF-κB, IL-6 ve NLRP3 mRNA ekspresyonu sağlıklı grup (H) ile karşılaştırıldığında azalmış olsa da (P<0.05) NF-κB, IL-6 ve NLRP3 mRNA ekspresyonu sadece tocilizumab uygulanan grupta (H+TCZ) arttı (P<0.05). A. baumannii enfeksiyonunda tocilizumab kullanımı, steroidlerle immünsüprese edilmiş ratlarda infl amatuar sitokinleri önemli ölçüde azalttı. Azalan sitokinlere rağmen, A. baumannii’nin enfeksiyona bağlı akciğer hasarını arttırdığı gösterilmiştir. Bu, steroid kullanan veya yakın zamanda steroid kullanmış hastalarda tocilizumabın fırsatçı enfeksiyon nedeniyle organ hasarını artırabileceğini düşündürmektedir
Anahtar Kelime:

Belge Türü: Makale Makale Türü: Araştırma Makalesi Erişim Türü: Erişime Açık
  • 1. Baumann P, Doudoroff M, Stanier RY: A study of the Moraxella group II. Oxidative-negative species (genus Acinetobacter). J Bacteriol, 95 (5): 1520-1541, 1968. DOI: 10.1128/jb.95.5.1520-1541.1968
  • 2. Bouvet PJM, Grimont PAD: Taxonomy of the genus Acinetobacter with the recognition of Acinetobacter baumannii sp. nov., Acinetobacter haemolyticus sp. nov., Acinetobacter johnsonii sp. nov., and Acinetobacter junii sp. nov. and emended descriptions of Acinetobacter calcoaceticus and Acinetobacter lwoffii. Int J Syst Evol, 36 (2): 228-240, 1986. DOI: 10.1099/00207713-36-2-228
  • 3. Dijkshoorn L, Nemec A, Seifert H: An increasing threat in hospitals: Multidrug-resistant Acinetobacter baumannii. Nat Rev Microbiol, 5 (12): 939-951, 2007. DOI: 10.1038/nrmicro1789
  • 4. Munoz-Price LS, Weinstein RA: Acinetobacter infection. N Engl J Med, 358 (12): 1271-1281, 2008. DOI: 10.1056/NEJMra070741
  • 5. Wong D, Nielsen TB, Bonomo RA, Pantapalangkoor P, Luna B, Spellberg B: Clinical and pathophysiological overview of Acinetobacter infections: A century of challenges. Clin Microbiol Rev, 30 (1): 409-447, 2017. DOI: 10.1128/CMR.00058-16
  • 6. Chung DR, Song JH, Kim SH, Thamlikitkul V, Huang SG, Wang H, So TMK, Yasin RMD, Hsueh PR, Carlos CC, Hsu LY, Buntaran L, Lalitha MK, Kim MJ, Choi LY, Kim SII, Ko KS, Kang CI, Peck KR, Asian Network for Surveillance of Resistant Pathogens Study Group: High prevalence of multidrug-resistant nonfermenters in hospital-acquired pneumonia in Asia. Am J Respir Crit Care Med, 184 (12): 1409-1417, 2011. DOI: 10.1164/ rccm.201102-0349OC
  • 7. Tognim MCB, Andrade SS, Silbert S, Gales AC, Jones RN, Sader HS: Resistance trends of Acinetobacter spp. in Latin America and characterization of international dissemination of multi-drug resistant strains: Five-year report of the SENTRY Antimicrobial Surveillance Program. Int J Infect Dis, 8 (5): 284-291, 2004. DOI: 10.1016/j.ijid.2003.11.009
  • 8. Van Dessel H, Dijkshoorn L, van der Reijden T, Bakker N, Paauw A, van den Broek P, Verhoef J, Brisse S: Identification of a new geographically widespread multiresistant Acinetobacter baumannii clone from European hospitals. Res Microbiol, 155 (2): 105-112, 2004. DOI: 10.1016/ j.resmic.2003.10.003
  • 9. Gaddy JA, Arivett BA, McConnell MJ, López-Rojas R, Pachón J, Actis LA: Role of acinetobactin-mediated iron acquisition functions in the interaction of Acinetobacter baumannii strain ATCC 19606T with human lung epithelial cells, Galleria mellonella caterpillars, and mice. Infect Immun, 80 (3): 1015-1024, 2012. DOI: 10.1128/IAI.06279-11
  • 10. Howard A, O’Donoghue M, Feeney A, Sleator RD: Acinetobacter baumannii: An emerging opportunistic pathogen. Virulence, 3 (3): 243- 250, 2012. DOI: 10.4161/viru.19700
  • 11. McConnell MJ, Actis L, Pachón J: Acinetobacter baumannii: Human infections, factors contributing to pathogenesis and animal models. FEMS Microbiol Rev, 37 (2): 130-155, 2013. DOI: 10.1111/j.1574-6976. 2012.00344.x
  • 12. Mortensen BL, Skaar EP: The contribution of nutrient metal acquisition and metabolism to Acinetobacter baumannii survival within the host. Front Cell Infect Microbiol, 3:95, 2013. DOI: 10.3389/fcimb. 2013.00095
  • 13. Mortensen BL, Skaar EP: Host-microbe interactions that shape the pathogenesis of Acinetobacter baumannii infection. Cell Microbiol, 14 (9): 1336-1344, 2012. DOI: 10.1111/j.1462-5822.2012.01817.x
  • 14. Seed KD: Battling phages: How bacteria defend against viral attack. PLoS Pathog, 11 (6): e1004847, 2015. DOI: 10.1371/journal.ppat.1004847
  • 15. Weber BS, Hennon SW, Wright MS, Scott NE, de Berardinis V, Foster LJ, Ayala JA, Adams MD, Feldman MF: Genetic dissection of the type VI secretion system in Acinetobacter and identification of a novel peptidoglycan hydrolase, TagX, required for its biogenesis. MBio, 7 (5): e01253-16, 2016. DOI: 10.1128/mBio.01253-16
  • 16. Sousa C, Botelho J, Silva L, Grosso F, Nemec A, Lopes J, Peixe L: MALDI-TOF MS and chemometric based identification of the Acinetobacter calcoaceticus-Acinetobacter baumannii complex species. Int J Med Microbiol, 304 (5-6): 669-677, 2014. DOI: 10.1016/j.ijmm.2014.04.014
  • 17. Vickers NJ: Animal communication: When I’m calling you, will you answer too? Curr Biol, 27 (14): R713-R715, 2017. DOI: 10.1016/j.cub. 2017.05.064
  • 18. Cerqueira GM, Peleg AY: Insights into Acinetobacter baumannii pathogenicity. IUBMB Life, 63 (12): 1055-1060, 2011. DOI: 10.1002/iub.533
  • 19. Park JH, Lee HK: Re-analysis of single cell transcriptome reveals that the NR3C1-CXCL8-neutrophil axis determines the severity of COVID-19. Front Immunol, 11: 2145, 2020. DOI: 10.3389/fimmu.2020.02145
  • 20. Meduri GU, Annane D, Confalonieri M, Chrousos GP, Rochwerg B, Busby A, Ruaro B, Meibohm B: Pharmacological principles guiding prolonged glucocorticoid treatment in ARDS. Intensive Care Med, 46 (12): 2284-2296, 2020. DOI: 10.1007/s00134-020-06289-8
  • 21. García-Patiño MG, García-Contreras R, Licona-Limón P: The immune response against Acinetobacter baumannii, an emerging pathogen in nosocomial infections. Front Immunol, 8:441, 2017. DOI: 10.3389/ fimmu.2017.00441
  • 22. Chen W: Host innate immune responses to Acinetobacter baumannii infection. Front Cell Infect Microbiol, 10:486, 2020. DOI: 10.3389/fcimb. 2020.00486
  • 23. Rokni M, Hamblin MR, Rezaei N: Cytokines and COVID-19: friends or foes? Hum Vaccin Immunother, 16 (10): 2363-2365, 2020. DOI: 10.1080/ 21645515.2020.1799669
  • 24. Cortegiani A, Ippolito M, Greco M, Granone V, Protti A, Gregoretti C, Giarratano A, Einav S, Cecconi M: Rationale and evidence on the use of tocilizumab in COVID-19: A systematic review. Pulmonology, 27 (1): 52- 66, 2021. DOI: 10.1016/j.pulmoe.2020.07.003
  • 25. Ramzy D, Tumiati LC, Tepperman E, Sheshgiri R, Jackman J, Badiwala M, Rao V: Dual immunosuppression enhances vasomotor injury: Interactive effect between endothelin-1 and nitric oxide bioavailability. J Thorac Cardiovasc Surg, 135 (4): 938-944, 2008. DOI: 10.1016/j.jtcvs.2007.09.075
  • 26. Chen KL, Lv ZY, Yang HW, Liu Y, Long FW, Zhou B, Sun XF, Peng ZH, Zhou ZG, Li Y: Effects of tocilizumab on experimental severe acute pancreatitis and associated acute lung injury. Crit Care Med, 44 (8):e664-e677, 2016. DOI: 10.1097/CCM.0000000000001639
  • 27. Wang Y, Zhang X, Feng X, Liu X, Deng L, Liang ZA: Expression of toll-like receptor 4 in lungs of immune-suppressed rat with Acinetobacter baumannii infection. Exp Ther Med, 12 (4): 2599-2605, 2016. DOI: 10.3892/ etm.2016.3624
  • 28. Keskin H, Keskin F, Tavaci T, Halici H, Yuksel TN, Ozkaraca M, Bilen A, Halici Z: Neuroprotective effect of roflumilast under cerebral ischaemia/reperfusion injury in juvenile rats through NLRP‐mediated inflammatory response inhibition. Clin Exp Pharmacol Physiol, 48 (8): 1103-1110, 2021. DOI: 10.1111/1440-1681.13493
  • 29. Livak KJ, Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2-ΔΔCT method. Methods, 25 (4): 402-408, 2001. DOI: 10.1006/meth.2001.1262
  • 30. Bilen A, Calik I, Yayla M, Dincer B, Tavaci T, Cinar I, Bilen H, Cadirci E, Halici Z, Mercantepe F: Does daily fasting shielding kidney on hyperglycemia-related inflammatory cytokine via TNF-α, NLRP3, TGF-β1 and VCAM-1 mRNA expression. Int J Biol Macromol, 190, 911-918, 2021. DOI: 10.1016/j.ijbiomac.2021.08.216
  • 31. Keskin H, Tavaci T, Halici H, Yuksel TN, Ozkaraca M, Bilen A, Kose D, Mendil AS, Halici Z: Early administration of milrinone ameliorates lung and kidney injury during sepsis in juvenile rats. Pediatr Int, 2021 (Article in Press). DOI: 10.1111/ped.14917
  • 32. Almomani BA, McCullough A, Gharaibeh R, Samrah S, Mahasneh F: Incidence and predictors of 14-day mortality in multidrug-resistant Acinetobacter baumannii in ventilator-associated pneumonia. J Infect Dev Ctries, 9 (12): 1323-1330, 2015. DOI: 10.3855/jidc.681
  • 33. Joly-Guillou ML, Wolff M, Pocidalo JJ, Walker F, Carbon C: Use of a new mouse model of Acinetobacter baumannii pneumonia to evaluate the postantibiotic effect of imipenem. Antimicrob Agents Chemother, 41 (2): 345-351, 1997. DOI: 10.1128/AAC.41.2.345
  • 34. Qiu H, KuoLee R, Harris G, Chen W: Role of NADPH phagocyte oxidase in host defense against acute respiratory Acinetobacter baumannii infection in mice. Infect Immun, 77 (3): 1015-1021, 2009. DOI: 10.1128/ IAI.01029-08
  • 35. Kumar H, Kawai T, Akira S: Pathogen recognition by the innate immune system. Int Rev Immunol, 30 (1): 16-34, 2011. DOI: 10.3109/ 08830185.2010.529976
  • 36. Kimura A, Naka T, Nakahama T, Chinen I, Masuda K, Nohara K, Fujii-Kuriyama Y, Kishimoto T: Aryl hydrocarbon receptor in combination with Stat1 regulates LPS-induced inflammatory responses. J Exp Med, 206 (9): 2027-2035, 2009. DOI: 10.1084/jem.20090560
  • 37. Meduri GU: Clinical review: A paradigm shift: The bidirectional effect of inflammation on bacterial growth. Clinical implications for patients with acute respiratory distress syndrome. Crit Care, 6 (1): 24-29, 2002. DOI: 10.1186/cc1450
  • 38. Meduri GU, Kanangat S, Bronze M, Patterson DR, Meduri CU, Pak C, Tolley EA, Schaberg DR: Effects of methylprednisolone on intracellular bacterial growth. Clin Diagn Lab Immunol, 8 (6): 1156-1163, 2001. DOI: 10.1128/CDLI.8.6.1156-1163.2001
  • 39. Tongyoo S, Permpikul C, Mongkolpun W, Vattanavanit V, Udompanturak S, Kocak M, Meduri GU: Hydrocortisone treatment in early sepsis-associated acute respiratory distress syndrome: Results of a randomized controlled trial. Crit Care, 20:329, 2016. DOI: 10.1186/s13054- 016-1511-2
  • 40. Sugui JA, Pardo J, Chang YC, Zarember KA, Nardone G, Galvez EM, Müllbacher A, Gallin JI, Simon MM, Kwon-Chung KJ: Gliotoxin is a virulence factor of Aspergillus fumigatus: gliP deletion attenuates virulence in mice immunosuppressed with hydrocortisone. Eukaryot Cell, 6 (9): 1562-1569, 2007. DOI: 10.1128/EC.00141-07
  • 41. Wu CL, Lee YL, Chang KM, Chang GC, King SL, Chiang CD, Niederman MS: Bronchoalveolar interleukin-1β: A marker of bacterial burden in mechanically ventilated patients with community-acquired pneumonia. Crit Care Med, 31 (3): 812-817, 2003. DOI: 10.1097/01. CCM.0000054865.47068.58
  • 42. Bergogne-Berezin E, Towner K: Acinetobacter spp. as nosocomial pathogens: Microbiological, clinical, and epidemiological features. Clin Microbiol Rev, 9 (2): 148-165, 1996. DOI: 10.1128/CMR.9.2.148
  • 43. Kang S, Tanaka T, Kishimoto T: Therapeutic uses of anti-interleukin-6 receptor antibody. Int Immunol, 27 (1): 21-29, 2015. DOI: 10.1093/intimm/ dxu081
  • 44. Giacobbe DR, Battaglini D, Ball L, Brunetti I, Bruzzone B, Codda G, Crea F, De Maria A, Dentone C, Di Biagio A, Icardi G, Magnasco L, Marchese A, Mikulska M, Orsi A, Patroniti N, robba C, Signori A, Taramasso L, Vena A, Pelosi P, Bassetti M: Bloodstream infections in critically ill patients with COVID‐19. Eur J Clin Invest, 50 (10): e13319, 2020. DOI: 10.1111/eci.133
APA ÇELEBİ D, Halici Z, ÇELEBİ Ö, Akgün N, Keskin H, CINAR I, halıcı i, Cinisli K, yildirim S (2022). Effect of Tocilizumab on Acinetobacter baumannii Lung Infection in an Immunosuppressed Rat Model. , 87 - 96. 10.9775/kvfd.2021.26491
Chicago ÇELEBİ Demet,Halici Zekai,ÇELEBİ Özgür,Akgün Nurullah,Keskin Halil,CINAR Irfan,halıcı iclal,Cinisli Kağan Tolga,yildirim Serkan Effect of Tocilizumab on Acinetobacter baumannii Lung Infection in an Immunosuppressed Rat Model. (2022): 87 - 96. 10.9775/kvfd.2021.26491
MLA ÇELEBİ Demet,Halici Zekai,ÇELEBİ Özgür,Akgün Nurullah,Keskin Halil,CINAR Irfan,halıcı iclal,Cinisli Kağan Tolga,yildirim Serkan Effect of Tocilizumab on Acinetobacter baumannii Lung Infection in an Immunosuppressed Rat Model. , 2022, ss.87 - 96. 10.9775/kvfd.2021.26491
AMA ÇELEBİ D,Halici Z,ÇELEBİ Ö,Akgün N,Keskin H,CINAR I,halıcı i,Cinisli K,yildirim S Effect of Tocilizumab on Acinetobacter baumannii Lung Infection in an Immunosuppressed Rat Model. . 2022; 87 - 96. 10.9775/kvfd.2021.26491
Vancouver ÇELEBİ D,Halici Z,ÇELEBİ Ö,Akgün N,Keskin H,CINAR I,halıcı i,Cinisli K,yildirim S Effect of Tocilizumab on Acinetobacter baumannii Lung Infection in an Immunosuppressed Rat Model. . 2022; 87 - 96. 10.9775/kvfd.2021.26491
IEEE ÇELEBİ D,Halici Z,ÇELEBİ Ö,Akgün N,Keskin H,CINAR I,halıcı i,Cinisli K,yildirim S "Effect of Tocilizumab on Acinetobacter baumannii Lung Infection in an Immunosuppressed Rat Model." , ss.87 - 96, 2022. 10.9775/kvfd.2021.26491
ISNAD ÇELEBİ, Demet vd. "Effect of Tocilizumab on Acinetobacter baumannii Lung Infection in an Immunosuppressed Rat Model". (2022), 87-96. https://doi.org/10.9775/kvfd.2021.26491
APA ÇELEBİ D, Halici Z, ÇELEBİ Ö, Akgün N, Keskin H, CINAR I, halıcı i, Cinisli K, yildirim S (2022). Effect of Tocilizumab on Acinetobacter baumannii Lung Infection in an Immunosuppressed Rat Model. Kafkas Üniversitesi Veteriner Fakültesi Dergisi, 28(1), 87 - 96. 10.9775/kvfd.2021.26491
Chicago ÇELEBİ Demet,Halici Zekai,ÇELEBİ Özgür,Akgün Nurullah,Keskin Halil,CINAR Irfan,halıcı iclal,Cinisli Kağan Tolga,yildirim Serkan Effect of Tocilizumab on Acinetobacter baumannii Lung Infection in an Immunosuppressed Rat Model. Kafkas Üniversitesi Veteriner Fakültesi Dergisi 28, no.1 (2022): 87 - 96. 10.9775/kvfd.2021.26491
MLA ÇELEBİ Demet,Halici Zekai,ÇELEBİ Özgür,Akgün Nurullah,Keskin Halil,CINAR Irfan,halıcı iclal,Cinisli Kağan Tolga,yildirim Serkan Effect of Tocilizumab on Acinetobacter baumannii Lung Infection in an Immunosuppressed Rat Model. Kafkas Üniversitesi Veteriner Fakültesi Dergisi, vol.28, no.1, 2022, ss.87 - 96. 10.9775/kvfd.2021.26491
AMA ÇELEBİ D,Halici Z,ÇELEBİ Ö,Akgün N,Keskin H,CINAR I,halıcı i,Cinisli K,yildirim S Effect of Tocilizumab on Acinetobacter baumannii Lung Infection in an Immunosuppressed Rat Model. Kafkas Üniversitesi Veteriner Fakültesi Dergisi. 2022; 28(1): 87 - 96. 10.9775/kvfd.2021.26491
Vancouver ÇELEBİ D,Halici Z,ÇELEBİ Ö,Akgün N,Keskin H,CINAR I,halıcı i,Cinisli K,yildirim S Effect of Tocilizumab on Acinetobacter baumannii Lung Infection in an Immunosuppressed Rat Model. Kafkas Üniversitesi Veteriner Fakültesi Dergisi. 2022; 28(1): 87 - 96. 10.9775/kvfd.2021.26491
IEEE ÇELEBİ D,Halici Z,ÇELEBİ Ö,Akgün N,Keskin H,CINAR I,halıcı i,Cinisli K,yildirim S "Effect of Tocilizumab on Acinetobacter baumannii Lung Infection in an Immunosuppressed Rat Model." Kafkas Üniversitesi Veteriner Fakültesi Dergisi, 28, ss.87 - 96, 2022. 10.9775/kvfd.2021.26491
ISNAD ÇELEBİ, Demet vd. "Effect of Tocilizumab on Acinetobacter baumannii Lung Infection in an Immunosuppressed Rat Model". Kafkas Üniversitesi Veteriner Fakültesi Dergisi 28/1 (2022), 87-96. https://doi.org/10.9775/kvfd.2021.26491